The candidate's long-term objective is to become an independent investigator, focusing on the use of novel treatments and strategies to improve the survival of patients with myeloid malignancies. There will be approximately 12,000 new cases of acute myeloid leukemia (AML) in the United States in 2006. Over 60% of patients diagnosed with AML are over the age of 60. Older adults with AML characteristically have poor prognosis disease, limited treatment options, and a high rate of induction-related complications. While complete remissions can be achieved with standard chemotherapy, long-term survival is extremely limited. Laboratory studies demonstrate that primitive leukemia cells and leukemia cell lines are sensitive to proteasome inhibition. In our phase I trial, we established that the novel proteasome inhibitor, bortezomib, can be safely combined with induction chemotherapy in patients with AML. However, data regarding the efficacy of bortezomib-containing regimens in AML and patient subtypes likely to respond are lacking. We hypothesize that proteasome inhibition will augment the clinical response to standard chemotherapy in AML and that the probability of remission induction can be predicted based on the bone marrow molecular expression profile. We propose to i) determine the clinical efficacy of bortezomib in combination with standard antileukemia therapy using two clinical trials, and ii) define molecular markers correlated with clinical response using microarray analyses of pretreatment bone marrow samples. These specific aims will be achieved under the mentorship of Dr. David Scadden, a leader in hematologic malignancies. The guidance of an outstanding research advisory committee and collaboration with a team experienced in functional genomics will further ensure success. Completion of these aims and the career development plan will prepare the candidate for an independent research career. This project has important health relatedness: AML is a disease of older adults for which treatment has varied little in the last two decades, and from which most patients ultimately die. We will use the results of these trials to determine if proteasome inhibition will be studied in future Phase III trials in patients with AML. The identification of molecular markers correlated with response will further understanding of leukemia pathogenesis and mechanisms of treatment resistance and will be used to develop prognostic assays for clinical use. [unreadable] [unreadable] [unreadable]